Diagnosis and management of Addison’s disease: insights gained from a large South African cohort

The prevalence of Addison’s disease in South Africa is lower than in Western countries. This is concerning, since patients could be dying, undiagnosed. Enhanced awareness of this highly treatable condition is warranted. The epidemiology, aetiology, clinical presentation, screening and management of Addison’s disease are discussed. Autoimmunity predominated as the underlying aetiology mostly in patients of European descent. A low threshold is required for screening, intervention and follow-up of all patients for cardiovascular risk factors, given the atherogenic profile observed among Addison’s disease sufferers in South Africa. Peer reviewed. (Submitted: 2011-05-30, Accepted: 2011-07-13) JEMDSA 2011;16(2):86-92 Review Article: Diagnosis and management of Addison’s disease Review Article: Diagnosis and management of Addison’s disease 87 2011 Volume 16 No 2 JEMDSA hypoglycaemia (1%).14,15 In the South African cohort, similar to other studies, hyperpigmentation, nausea, vomiting and weight loss were the most prominent features.16,17 Screening for primary adrenal failure The adrenal cortex, responsible for the release of cortisol and androgens, is under the negative feedback control of adrenocorticotropic hormone (ACTH), while the release of aldosterone is controlled by the renin-angiotensin II system. Progressive functional deterioration, as in autoimmune destruction of the adrenal cortex, results in diminished functional adrenal reserve, as shown by reduced plasma concentration of cortisol and aldosterone in association with an increased ACTH and renin release.18 The short synthetic ACTH stimulation test is regarded as the most reliable diagnostic test for chronic adrenal hypofunction. Synthetic ACTH can be injected intravenously or intramuscularly,19,20 but the dosage used, whether 1 μg or 250 μg, is vastly supraphysiological. Nevertheless, the 250 μg ACTH stimulation test provides the best sensitivity and specificity for confirmation of primary adrenal insufficiency. Subjects who have either basal or stimulated cortisol levels in excess of 500 nmol/l, do not have overt Addison’s disease.1,20 However, when an early morning (between 07h00 and 09h00) plasma cortisol is less than 165 nmol/l and a simultaneously taken plasma ACTH is elevated, no further confirmatory test is needed.1 The short synthetic ACTH stimulation test can also be used to diagnose secondary hypoadrenalism. With regard to the dose of ACTH to be used, a meta-analysis showed that the low-dose (1 μg) and the standard-dose (250 μg) ACTH stimulation test performed similarly, but the receiver operating curves using the 1 μg performed slightly superiorly in ruling out hypothalamic-pituitary adrenal axis insufficiency. However, the differences were clinically unimportant.21 Betterle et al proposed that subclinical autoimmune adrenalitis may evolve through three defined stages: stage 1, when both ACTH and basal plasma cortisol levels are normal, with concomitant elevated plasma renin activity and reduced or normal aldosterone levels; stage 2, when ACTH levels are normal but the peak stimulated plasma cortisol level is reduced; and stage 3, when the ACTH level is elevated through compensation but the basal plasma cortisol is reduced. Should stress, surgery, pregnancy, infection or trauma coexist in stage 3 of subclinical disease, overt clinical hypoadrenalism may manifest. Adrenal cortical mass declines throughout these predetermined subclinical stages.18 Subclinical hypoadrenalism should be considered when the ratio of ACTH (pmol/l) to cortisol (nmol/l) is increased to greater than 0.028.22 This is evident in early autoimmune primary adrenal insufficiency, when patients exhibit reduced sensitivity to low-dose ACTH stimulation.23 Patients with autoimmune polyglandular syndromes (APS) without Addison’s disease are at increased risk of subsequently developing Addison’s disease. The presence of either adrenocortical autoantibodies (ACA) or 21-hydroxylase autoantibodies in this subgroup represents a good marker of developing subsequent Addison’s disease, which was found to be greater in coexistent hypoparathyroidism than either type 1 diabetes mellitus and/ or autoimmune thyroid disease.18 However, the presence of either circulating ACA or 21-hydroxylase antibodies does not invariably indicate that adrenalitis or incipient hypoadrenalism will occur. For example, a baby born to a mother who had ACA and 21-hydroxylase autoantibodies, Addison’s disease and coexisting hypothyroidism (APS2) did not develop either clinical or subclinical hypoadrenalism until 34 months of age, suggesting that an additional factor other than positive adrenal autoantibodies is required to induce Addison’s disease.24 In Padua, Italy, the cumulative risk of developing autoimmune Addison’s disease was 48.5% among ACA-positive subjects, identifying a subgroup in which screening using 250 μg ACTH stimulation test needs to be performed periodically.25 It has not been our routine practice to screen for adrenal autoantibodies in patients with APS without Addison’s disease, except in the research setting, where only 3% were found to have positive adrenal autoantibodies.